Activators of epithelial Na+ channels inhibit cytosolic feedback control. Evidence for the existence of a G protein-coupled receptor for cytosolic Na+

J Membr Biol. 1998 Apr 1;162(3):225-32. doi: 10.1007/s002329900360.

Abstract

We have previously shown that epithelial Na+ channels in mouse mandibular gland duct cells are controlled by cytosolic Na+ and Cl-, acting, respectively, via Go and Gi proteins. Since we found no evidence for control of epithelial Na+ channels by extracellular Na+ ([Na+]o), our findings conflicted with the long-held belief that Na+ channel activators, such as sulfhydryl reagents, like para-chloromercuriphenylsulfonate (PCMPS), and amiloride analogues, like benzimidazolylguanidinium (BIG) and 5-N-dimethylamiloride (DMA), induce their effects by blocking an extracellular channel site which otherwise inhibits channel activity in response to increasing [Na+]o. Instead, we now show that PCMPS acts by rendering epithelial Na+ channels refractory to inhibition by activated G proteins, thereby eliminating the inhibitory effects of cytosolic Na+ and Cl- on Na+ channel activity. We also show that BIG, DMA, and amiloride itself, when applied from the cytosolic side of the plasma membrane, block feedback inhibition of Na+ channels by cytosolic Na+, while leaving inhibition by cytosolic Cl- unaffected. Since the inhibitory effects of BIG and amiloride are overcome by the inclusion of the activated alpha-subunit of Go in the pipette solution, we conclude that these agents act by blocking a previously unrecognized intracellular Na+ receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Chloromercuribenzenesulfonate / pharmacology
  • Amiloride / analogs & derivatives
  • Amiloride / pharmacology
  • Animals
  • Anions
  • Cells, Cultured
  • Cytosol / metabolism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / physiology
  • Epithelium / physiology
  • GTP-Binding Proteins / metabolism*
  • Guanidines / pharmacology
  • Male
  • Mice
  • Receptors, Cell Surface / metabolism*
  • Salivary Ducts / cytology
  • Sodium Channels / drug effects*
  • Sodium Channels / physiology
  • Sulfhydryl Reagents / pharmacology

Substances

  • Anions
  • Guanidines
  • Receptors, Cell Surface
  • Sodium Channels
  • Sulfhydryl Reagents
  • 5-dimethylamiloride
  • 2-benzimidazolylguanidine
  • 4-Chloromercuribenzenesulfonate
  • Amiloride
  • GTP-Binding Proteins